PROJECT SUMMARY/ABSTRACT There is ample preclinical evidence showing that ovarian hormones influence the neurobiological systems that mediate drug and alcohol reward which may contribute to the enhanced vulnerability of women to AUD; studies show that estrogen promotes and progesterone opposes alcohol reward. Yet, there is little conclusive empirical data from controlled human studies of alcohol effects and consumption in naturally-cycling women. Consequently, our understanding of how to prevent and better treat AUD among women is compromised, and new research approaches are needed. Recent findings suggest that periods of high hormonal flux during the menstrual cycle are associated with increased binge drinking. Oral contraceptives (OC) are medications containing synthetic ovarian hormones that suppress menstrual cycle-related fluctuations in endogenous hormones. So, endogenous estrogen and progesterone, and exogenous estradiol remain low across the cycle while synthetic progestins are high and stable. Studies of alcohol effects and consumption among women using OC in comparison to naturally cycling women will advance our understanding of how ovarian hormones influence AUD because there is greater power to detect effects of ovarian hormones against a background of low variability, and we can also compare relative hormone stability vs. variation. The long-term goal of this research is to better understand how ovarian hormones influence alcohol use, abuse, and the course of AUD among women. The objective of the proposed research is to determine how OC influence alcohol effects and consumption using controlled laboratory procedures. The working hypothesis is that synthetic progestins in oral contraceptives mimic the effects of natural progesterone thereby attenuating the rewarding and motivational effects of alcohol, and alcohol consumption. The rationale is that determining the influence of synthetic ovarian hormones (OC) on alcohol effects will provide a strong framework to pursue novel women-focused prevention and treatment approaches. The hypothesis will be tested by two specific aims; 1) Determine the influence of oral contraceptives on dose-dependent effects of alcohol, and alcohol self-administration using controlled human laboratory procedures, and 2) Determine the relationship between circulating levels of natural and synthetic ovarian hormones and alcohol effects and consumption. This plan of research is innovative because it will shift the focus of research on the effects of ovarian hormones on alcohol responses and consumption from endogenous to exogenous hormones. This will also be the first controlled study of alcohol effects and consumption among women using OC. The project is significant because it will substantially advance our understanding of how ovarian hormones influence alcohol effects and drinking, an important factor that contributes to sex differences in AUD. The findings will be clinically significant as they apply to a large proportion of US women who currently use hormonal contraceptives and will highlight the overlooked research area of synthetic hormones and AUD. Finally, positive findings that high stable synthetic progestin dampens alcohol reward will provide a framework for the development of therapies focused on female mechanisms.